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June 9, 2010
Raising Your HDL - Through the Brain?
For a long time now, people have been searching for a way to raise HDL levels (the so-called "good cholesterol"). Statins will lower your LDL, while raising HDL just a pinch, but no one has a good, robust way to do it. (Niacin is probably the closest thing, but not everyone can take it). Many have tried, and failed, with Pfizer's CETP inhibitor torcetrapib being the most notably horrendous.
Now there's a completely new way to regulate HDL, and it comes from a direction you might not expect: the brain. A new paper in Nature Neuroscience demonstrates that melanocortin signaling, ghrelin and GLP-1 change HDL levels, through both altered cholesterol synthesis and uptake. Since these are involved in a number of ways in food intake and metabolism, it makes sense (in retrospect) that there would be a lipoprotein connection, but this does seem to be a dramatically direct one. (More and more, it appears that many metabolic processes that were thought to be more peripheral are under some sort of central control, actually). As the authors put it:
An integrated neuroendocrine control of food intake, body weight and glucose homeostasis, as well as cholesterol metabolism and cardiovascular lipid exposure, would connect all of the hallmarks of the metabolic syndrome. Therapies promoting the increase of HDL levels have been proposed for the prevention of atherosclerosis in humans. . . We speculate that modulation of neuroendocrine circuits may offer therapeutic opportunities to prevent cardiovascular disease.
Yes, indeed. It's not going to be easy, though. Ghrelin and GLP-1 have already been looked at for diabetes and obesity therapy, and they're tricky to deal with. Small-molecule ghrelin antagonists are known - as I should know - and there have been many reports of melanocortin receptor ligands as well. Of course, the question will be how many other things you might mess with at the same time, but it's going to be very interesting and worthwhile to unravel these.
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